title: Combinational analysis of linkage and exome sequencing identifies the causative mutation in a Chinese family with congenital cataract.
abstract: BACKGROUND
  Congenital cataract is a Mendelian disorder that frequently causes blindness in infants. To date, various cataract-associated loci have been mapped; more than 30 genes have been identified by linkage analysis. However, the pathogenic loci in some affected families are still unknown, and new research strategies are needed. In this study, we used linkage-exome combinational analysis to further investigate the pedigree of a four-generation Chinese family with autosomal dominant coralliform cataract.
  
  
  METHODS
  We combined whole exome sequencing and linkage analysis to identify the causative mutation. The exome capture and next-generation sequencing were used to sequence the protein-coding regions in the genome of the proband to identify rare mutations, which were further screened for candidate mutations in linkage regions. Candidate mutations were independently verified for co-segregation in the whole pedigree using Sanger sequencing.
  
  
  RESULTS
  We identified a C to A transversion at nucleotide position c.70 in exon 2 of CRYGD, a cataract-associated gene. This mutation resulted in a threonine substitution for proline at amino acid residue 24.
  
  
  CONCLUSIONS
  We identified a missense P24T mutation in CRYGD that was responsible for coralliform cataract in our studied family. Our findings suggest that the combination of exome sequencing and linkage analysis is a powerful tool for identifying Mendelian disease mutations that might be missed by the classic linkage analysis strategy.
authors.affiliation: Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China. fusb@ems.hrbmu.edu.cn.
authors.forename: Xueyuan
authors.initials: X
authors.lastname: Jia
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Bai
authors.forename: Linghan
authors.initials: L
authors.lastname: Gao
authors.forename: Xuelong
authors.initials: X
authors.lastname: Zhang
authors.forename: Haiming
authors.initials: H
authors.lastname: Sun
authors.forename: Donglin
authors.initials: D
authors.lastname: Sun
authors.forename: Rongwei
authors.initials: R
authors.lastname: Guan
authors.forename: Wenjing
authors.initials: W
authors.lastname: Sun
authors.forename: Lidan
authors.initials: L
authors.lastname: Xu
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Yue
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.forename: Songbin
authors.initials: S
authors.lastname: Fu
mesh_terms: D044466:Asian People / Q000235:genetics*; D002386:Cataract / Q000151:congenital / Q000235:genetics* / Q000473:pathology; D002681:China; D005091:Exons; D008040:Genetic Linkage; D006239:Haplotypes; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D020125:Mutation, Missense; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D038222:gamma-Crystallins / Q000235:genetics*
chemical_list: C504903:CRYGD protein, human; D038222:gamma-Crystallins